Inflammatory Skin And Bowel Disease, Neonatal, 2

A number sign (#) is used with this entry because of evidence that neonatal inflammatory skin and bowel disease-2 (NISBD2) is caused by homozygous mutation in the EGFR gene (131550) on chromosome 7p11. One such family has been reported.

For a discussion of genetic heterogeneity of neonatal inflammatory skin and bowel disease, see NISBD1 (614328).

Clinical Features

Campbell et al. (2014) studied a male infant, born to Polish Roma parents, who from birth had widespread erosions affecting his trunk and limbs and later developed papules and pustules, with frequent Staphylococcus aureus infections of the skin. He also had lifelong watery diarrhea and respiratory difficulties, and at 1 year of age exhibited failure to thrive. He had loss of scalp hair but long eyelashes (trichomegaly); no nail abnormalities were seen. He had undergone surgery for probable coarctation of the aorta and was hypertensive. He had recurrent bronchiolitis, and pulmonary infection with Pseudomonas aeruginosa required tracheostomy and oxygen. He had bilateral renal enlargement on ultrasound but no obstruction. Although he had no specific food allergies, he was unable to tolerate solids due to diarrhea and vomiting, and ultimately required total parenteral nutrition. Venous access lines frequently became clotted, and he developed deep vein thromboses. He died at 2.5 years of age due to cutaneous and pulmonary infections and electrolyte imbalance. Light microscopy of nonlesional skin from the patient showed mild acanthosis and slight widening between adjacent keratinocytes compared to controls; electron microscopy revealed intercellular edema from the basal to mid-spinous layer and a slight decrease in the number of gap junctions, but no structural or numerical abnormalities in hemidesmosome or desmosome cell junctions. Skin immunolabeling demonstrated a marked reduction in staining intensity for the desmosomal proteins desmoglein-1 (125670) and plakophilin-1 (601975), as well as altered labeling patterns for markers of terminal differentiation in the epidermis, including profilaggrin (135940), involucrin (147360), and keratin-10 (148080). Immunofluorescence microscopy to assess EGFR in patient skin showed a markedly altered staining pattern with loss of cell peripheral membrane labeling and more cytoplasmic or perinuclear distribution, in contrast to strong cell membrane localization of EGFR in control skin.

Molecular Genetics

By whole-exome sequencing of DNA from a Polish Roma boy who died from neonatal inflammatory skin and bowel disease, Campbell et al. (2014) identified homozygosity for a missense mutation in the EGFR gene (G428D; 131550.0007). His unaffected mother was heterozygous for the mutation, which was not present in an unaffected sib; no DNA from the father was available. The mutation was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 900 unrelated European in-house control exomes.